You are here

eLetters

547 e-Letters

I read with great interest the paper by Jamjoom et al.[1] The authors have done commendable work in establishing a national external ventricular drain related infection (ERI) rate and elucidating the factors influencing it in the largest prospective multicentre study. However, some questions have been left unanswered in this respect.
One of the contributing factors to a low ERI rate in the study could have been the fact that majority (98.6%) of EVDs were inserted in the operating theatre. In their single centre retrospective study of 84 patients, Arabi et al[2] found that placement outside operating rooms was associated with a trend towards higher ERIs. Clark et al[3], in their retrospective review of complications of intracranial pressure monitoring in 140 trauma patients, noted that the incidence of major infectious complications (eg. clinical ventriculitis, subdural empyema, brain abscesses) was higher in the groups in which the catheter was placed in the intensive care unit. A randomised control trial would better examine the importance of this finding.
In this study by Jamjoom et al[1], the authors found no significant difference between infected and uninfected cases with regard to the length of tunnelling. However, recent evidence although weak, points towards a preventive benefit of long tunnel EVDs over short tunnel EVDs.[4,5] Hence, a discussion about the role of tunnelling length in ERIs is felt missing in the paper.
Korinek et al, in their stud...

I read with great interest the paper by Jamjoom et al.[1] The authors have done commendable work in establishing a national external ventricular drain related infection (ERI) rate and elucidating the factors influencing it in the largest prospective multicentre study. However, some questions have been left unanswered in this respect.
One of the contributing factors to a low ERI rate in the study could have been the fact that majority (98.6%) of EVDs were inserted in the operating theatre. In their single centre retrospective study of 84 patients, Arabi et al[2] found that placement outside operating rooms was associated with a trend towards higher ERIs. Clark et al[3], in their retrospective review of complications of intracranial pressure monitoring in 140 trauma patients, noted that the incidence of major infectious complications (eg. clinical ventriculitis, subdural empyema, brain abscesses) was higher in the groups in which the catheter was placed in the intensive care unit. A randomised control trial would better examine the importance of this finding.
In this study by Jamjoom et al[1], the authors found no significant difference between infected and uninfected cases with regard to the length of tunnelling. However, recent evidence although weak, points towards a preventive benefit of long tunnel EVDs over short tunnel EVDs.[4,5] Hence, a discussion about the role of tunnelling length in ERIs is felt missing in the paper.
Korinek et al, in their study to test the effect of a strict protocol of care on ERI, have postulated that frequent manipulation of EVD increases the risk of related infections.[6] Since the study by Jamjoom et al[1] was a prospective study, this strength could have been utilised in determining the role of frequent manipulation of EVD (eg. dressing, flushing the system, administering intrathecal drugs) for purposes other than CSF sampling.
Lastly, an analysis of the role of perioperative systemic antibiotics as a preventive measure in ERI could have been done as the evidence is still controversial in this regard.[6]

We read with great interest the research paper published recently by Lotia et al. entitled “Leg stereotypy syndrome: phenomenology and prevalence”. 1 The study brings important new information about an intriguing newly identified condition, previously designated by the same group as leg stereotypy disorder2, defined as repetitive, rhythmical, stereotypic leg movements, particularly noticeable while sitting.1,2 The authors describe the phenomenology and prevalence of leg stereotypy syndrome (LSS) by evaluating a total of 92 individuals, 57 from the general population (control group) and 35 with different movement disorders (Parkinson´s disease, restless legs syndrome, Tourette´s syndrome, and tardive dyskinesia).1 LSS was found in 7% of the control group and 17% of the movement disorders group, concluding that in terms of prevalence, this is a common condition.1 Another interesting finding was that all but one (83 %) of the patients with LSS from the movement disorders group also had a diagnosis of attention deficit hyperactivity disorder (ADHD).1 Lotia and colleagues do not believe in a relationship between ADHD and LSS1 stating in the discussion that “while certain movements or fidgetiness can be observed in individuals with anxiety or ADHD, the presence of typical stereotyped movements has not been previously described with ADHD”.1 Our group is currently studying the frequency of abnormal involuntary movements in patients with ADHD, compared a control group, and our pre...

We read with great interest the research paper published recently by Lotia et al. entitled “Leg stereotypy syndrome: phenomenology and prevalence”. 1 The study brings important new information about an intriguing newly identified condition, previously designated by the same group as leg stereotypy disorder2, defined as repetitive, rhythmical, stereotypic leg movements, particularly noticeable while sitting.1,2 The authors describe the phenomenology and prevalence of leg stereotypy syndrome (LSS) by evaluating a total of 92 individuals, 57 from the general population (control group) and 35 with different movement disorders (Parkinson´s disease, restless legs syndrome, Tourette´s syndrome, and tardive dyskinesia).1 LSS was found in 7% of the control group and 17% of the movement disorders group, concluding that in terms of prevalence, this is a common condition.1 Another interesting finding was that all but one (83 %) of the patients with LSS from the movement disorders group also had a diagnosis of attention deficit hyperactivity disorder (ADHD).1 Lotia and colleagues do not believe in a relationship between ADHD and LSS1 stating in the discussion that “while certain movements or fidgetiness can be observed in individuals with anxiety or ADHD, the presence of typical stereotyped movements has not been previously described with ADHD”.1 Our group is currently studying the frequency of abnormal involuntary movements in patients with ADHD, compared a control group, and our preliminary results have demonstrated that legs and foot stereotypies are actually very common in patients with ADHD (30 % ) (Teive et al., unpublished data). In fact, lower limbs stereotypies, such as fidgeting and foot movements (crossed-knee jiggle and uni or bilateral toe tap) was previously characterized by Wender, as a suggestive sign of ADHD in adult patients, often referred to as Wender´s sign.3 We believe that these findings may contribute to the understanding and phenomenological characterization of the new neurological syndrome described by Lotia et al.
References:
1. Lotia M, York MK, Strutt AM, Jankovic J. Leg stereotypy syndrome: phenomenology and prevalence. J Neurol Neurosurg Psychiatry 2018; 0: 1-4. Doi: 10.1136/jnnp-2017-317057
2. Jankovic J. Leg stereotypy disorder. J Neurol Neurosurg Psychiatry 2016; 87: 220-221.
3. Wender PH. Attention deficit hyperactivity disorder in adults. Oxford University Press, New York, 1995, pp. 23

Imai et al. examined the association between the dosing regimen of oral prednisolone (PSL) and the achievement of minimal manifestation status or better on PSL <=5 mg/day lasting >6 months in patients with generalized myasthenia gravis (1). The authors classified 590 patients into high-dose, intermediate-dose and low-dose (n=166) groups, and logistic regression analysis was applied to know the prognosis of patients in low-dose group, by splitting observational period into 1 to 3 years of treatment. The authors concluded that a low-dose PSL regimen with early combination of other treatment options was significantly associated with good prognosis. I have two concerns about their study.

First, the dosing regimen of oral PSL should be considered with caution. Namely, the authors set the maximum dose of oral PSL in each group, and standard treatment schedule was selected after each patient was allocated. Mean daily dose of PSL does not become highest in high-dose group in the study, which happens in the study protocol. In addition, there is a possibility of higher frequency in patients with combination of other treatment options, when patients were registered into low-dose group. As the age of onset was higher and disease duration was shorter in patients with low-dose group, randomized allocation should be strictly conducted in further study.

Second, the number of events was not enough after 1 year observation, and higher odds ratios with wide ranges of con...

Imai et al. examined the association between the dosing regimen of oral prednisolone (PSL) and the achievement of minimal manifestation status or better on PSL <=5 mg/day lasting >6 months in patients with generalized myasthenia gravis (1). The authors classified 590 patients into high-dose, intermediate-dose and low-dose (n=166) groups, and logistic regression analysis was applied to know the prognosis of patients in low-dose group, by splitting observational period into 1 to 3 years of treatment. The authors concluded that a low-dose PSL regimen with early combination of other treatment options was significantly associated with good prognosis. I have two concerns about their study.

First, the dosing regimen of oral PSL should be considered with caution. Namely, the authors set the maximum dose of oral PSL in each group, and standard treatment schedule was selected after each patient was allocated. Mean daily dose of PSL does not become highest in high-dose group in the study, which happens in the study protocol. In addition, there is a possibility of higher frequency in patients with combination of other treatment options, when patients were registered into low-dose group. As the age of onset was higher and disease duration was shorter in patients with low-dose group, randomized allocation should be strictly conducted in further study.

Second, the number of events was not enough after 1 year observation, and higher odds ratios with wide ranges of confidence interval were observed. As the follow-up period become longer, odds ratios become small, although significance disappeared in comparison between low-dose and high-dose groups after 3 year observation. I suppose that confounders for the prognosis were not completely adjusted, and there is a limitation of study design in multicentre cross-sectional study.

I appreciate Dr Popkirov’s unique and interesting views and comments related to our paper [1]. This reminds me of the gating of sensory inputs at various levels of the nervous system, and their perception is not a passive but is a very active process. In addition to the fact that it is not possible to tickle oneself, other sensory phenomena associated with abnormal movements deserve mention. Restless legs syndrome is characterized by constant urge to move legs, and is successfully managed by dopamine agonists. Tics are also preceded by sensory symptoms. These could be examples of aberrant sensory inputs coming to the conscious level, which would normally be handled at subconscious pathways. At this moment, the exact role of the cerebellar pathway in these conditions is not clear, but should be investigated in the future aside from dystonia.

Dear Editor,
We read with great interest the article of Boentert et al.1 recently published on this journal. In their paper, the authors describe polysomnographic findings in a large series of non-ventilated patients with amyotrophic lateral sclerosis (ALS). One of the points the authors underscore is that in their patients most respiratory events during sleep were of the obstructive, and not of the central type. This finding is in agreement with what described by Kimura,2 but not by several other authors who found that most respiratory events were of the central type.3 Furthermore, the authors of this paper did not find that obstructive apneas were preferentially associated with bulbar ALS, similarly to David et al.4 but unlike what described by Santos et al.5 However, the tables in the article show that most of the respiratory events were hypopneas, whose type was not specified.
Criteria for scoring sleep disordered breathing events have changed over time, especially as regards hypopneas. Only recently a general rule for type of hypopnea, central or obstructive has been proposed. Obstructive hypopneas are those where at least one of three criteria is met during the event: presence of snoring, flow limitation demonstrated by a flattening of the nasal pressure derived flow signal, opposing thoracic and abdominal movements. Absence of all these criteria characterizes central hypopneas.6 However, standard criteria for apneas and hypopneas fit well to patients wi...

Dear Editor,
We read with great interest the article of Boentert et al.1 recently published on this journal. In their paper, the authors describe polysomnographic findings in a large series of non-ventilated patients with amyotrophic lateral sclerosis (ALS). One of the points the authors underscore is that in their patients most respiratory events during sleep were of the obstructive, and not of the central type. This finding is in agreement with what described by Kimura,2 but not by several other authors who found that most respiratory events were of the central type.3 Furthermore, the authors of this paper did not find that obstructive apneas were preferentially associated with bulbar ALS, similarly to David et al.4 but unlike what described by Santos et al.5 However, the tables in the article show that most of the respiratory events were hypopneas, whose type was not specified.
Criteria for scoring sleep disordered breathing events have changed over time, especially as regards hypopneas. Only recently a general rule for type of hypopnea, central or obstructive has been proposed. Obstructive hypopneas are those where at least one of three criteria is met during the event: presence of snoring, flow limitation demonstrated by a flattening of the nasal pressure derived flow signal, opposing thoracic and abdominal movements. Absence of all these criteria characterizes central hypopneas.6 However, standard criteria for apneas and hypopneas fit well to patients with sleep apnea syndromes, but may be difficult to use in patients with other disorders, and in particular in those with neuromuscular diseases.
The separate occurrence of central and obstructive hypopneas was reported in some ALS studies, although standard criteria were not applied. However, a sharp separation of obstructive and central hypopneas in patients with ALS may be difficult, either using standard criteria or not, and often factitious. A clear flattening of the flow signal may not be clearly identified with a weak flow signal. Paradoxical thoraco-abdominal movements may be the effect not only of upper airway narrowing but also of respiratory muscle weakness. Finally, perhaps most importantly, presence of obstruction during a hypopnea does not exclude a simultaneous reduction of respiratory drive, thus a concomitant central genesis of the event.
Even when dealing with apneas, the precise nature of an event in neuromuscular patients is often dubious based on its polygraphic appearance. In the International Classification of Sleep Disorders, central apneas are indicated as the result of a failure of ventilatory control centers to initiate ventilatory effort.7 However, in common practice central apneas are identified by the absence of respiratory movements on polygraphic recordings, although it may not be always easy to precisely identify the pathogenesis of an event based on its polygraphic expression. In neuromuscular patients, many apneas are associated with very small movements. That may lead different scorers to classify them as either central or obstructive. Some authors suggested to introduce the new category of “pseudocentral apneas” to indicate events occurring when the contraction of respiratory muscles is too weak to maintain breathing, which may be more often seen in phasic REM sleep.8 During these events, deflections in the traces of the respiratory movements are very small. Despite their polygraphic aspect resembles apneas more often of the central type, their pathogenesis depends more on peripheral that on central causes. This category of events is not taken in consideration by most authors studying neuromuscular patients. Probably, a non-uniform way to score respiratory events in ALS is one reason for some discrepancies among studies.
We are aware that a correct identification of central and obstructive events is important, because they require different ventilatory approaches that may have a strong influence on sleep quality, therapy acceptance and, in the long-term, disease evolution and survival. Use of positive expiratory pressure, which is mandatory when obstructive events are present, is not only useless, but also questionable in case of absence of upper airway obstruction, as it enhances patient-ventilator asynchronies and sympathetic nervous system tone during sleep.9
Possibly, criteria for scoring sleep disordered breathing events in non-ventilated patients with neuromuscular diseases should be better standardized. They could be useful to have a better agreement among physicians who evaluate polysomnographic recordings, and to better guide in the choice of an appropriate therapeutic strategy.

In their recent article on the pathogenesis of dystonia, Kaji and colleagues argue that aberrant cerebellar inputs can induce dystonic movement mediated by the basal ganglia.[1] In this framework, the sensory trick (geste antagoniste) leads to a realignment between predicted and actual sensory information, thus reduces (or overrides) the sensorimotor mismatch forwarded to the basal ganglia, and in turn alleviates dystonic contractions.
A similar model of sensorimotor mismatch response has been implicated in the physiology of being tickled[2]. Specifically, it has been proposed that the inability to tickle oneself is related to a sensory attenuation mediated by the cerebellum during self-generated tactile sensation[3]. This attenuation is proportional to the precision of the sensory prediction[4]. Whether the same cerebellar processes are responsible for the alleviation of dystonia during a sensory trick would be an interesting question to explore experimentally. At the risk of straining the analogy, one could even describe the postures and movements one produces when being tickled as dystonic-like. Neurologists are reminded of this when interpreting ambiguous plantar responses in very ticklish patients -- a problem that can be avoided by employing the patient's cerebellar sensory attentuation[5].

In their recent article on the pathogenesis of dystonia, Kaji and colleagues argue that aberrant cerebellar inputs can induce dystonic movement mediated by the basal ganglia.[1] In this framework, the sensory trick (geste antagoniste) leads to a realignment between predicted and actual sensory information, thus reduces (or overrides) the sensorimotor mismatch forwarded to the basal ganglia, and in turn alleviates dystonic contractions.
A similar model of sensorimotor mismatch response has been implicated in the physiology of being tickled[2]. Specifically, it has been proposed that the inability to tickle oneself is related to a sensory attenuation mediated by the cerebellum during self-generated tactile sensation[3]. This attenuation is proportional to the precision of the sensory prediction[4]. Whether the same cerebellar processes are responsible for the alleviation of dystonia during a sensory trick would be an interesting question to explore experimentally. At the risk of straining the analogy, one could even describe the postures and movements one produces when being tickled as dystonic-like. Neurologists are reminded of this when interpreting ambiguous plantar responses in very ticklish patients -- a problem that can be avoided by employing the patient's cerebellar sensory attentuation[5].

In our previous meta-analysis of cerebellar atrophy in seven major neurodegenerative conditions (Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP)) we investigated studies that reported grey matter (GM) loss in the cerebellum [1]. Consistent regions of atrophy were found in AD, ALS, FTD, MSA, and PSP but not HD or PD. In their comment on our meta-analysis, Sheng and Pan have argued that our method of selectively investigating studies that found cerebellar atrophy, rather than adopting a whole-brain approach, is “not optimal in a coordinate-based meta-analysis” [2]. They further cite previous whole-brain meta-analyses that did not identify clusters of cerebellar grey matter loss in patients [3-6].
Here, we argue that our approach was justified given our aim, which was to focus on cases where cerebellar atrophy was found in the respective disease groups in order to determine 1) if such atrophy followed a consistent, robust pattern, and 2) if atrophy patterns were disease-specific or generic, where possible relating them to symptomatology.
There are several reasons why we chose to focus on the cerebellum rather than adopting a whole-brain approach. First, the cerebellum is hardly a “region of interest” in the classical sense given its marked heterogeneity in terms of function and connectivity as we...

In our previous meta-analysis of cerebellar atrophy in seven major neurodegenerative conditions (Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP)) we investigated studies that reported grey matter (GM) loss in the cerebellum [1]. Consistent regions of atrophy were found in AD, ALS, FTD, MSA, and PSP but not HD or PD. In their comment on our meta-analysis, Sheng and Pan have argued that our method of selectively investigating studies that found cerebellar atrophy, rather than adopting a whole-brain approach, is “not optimal in a coordinate-based meta-analysis” [2]. They further cite previous whole-brain meta-analyses that did not identify clusters of cerebellar grey matter loss in patients [3-6].
Here, we argue that our approach was justified given our aim, which was to focus on cases where cerebellar atrophy was found in the respective disease groups in order to determine 1) if such atrophy followed a consistent, robust pattern, and 2) if atrophy patterns were disease-specific or generic, where possible relating them to symptomatology.
There are several reasons why we chose to focus on the cerebellum rather than adopting a whole-brain approach. First, the cerebellum is hardly a “region of interest” in the classical sense given its marked heterogeneity in terms of function and connectivity as well as its large cell count [7,8]. Using an ROI approach on the cerebellum is therefore not vastly different from conducting an analysis restricted to the neocortex, a practice that is abundant and well accepted. The vast majority of coordinates used in our analysis stemmed from whole-brain analyses and omitting the few studies with an ROI approach for the cerebellum is highly unlikely to affect the main clusters we identified.
Second, there is an abundance of coordinate-based meta-analyses using ROI approaches (see http://www.brainmap.org/pubs/), including one of the most influential papers into the functions of the cerebellum [8].
Third, the systematic literature search of papers investigating the diseases in question has revealed that many analyses were inherently biased against the cerebellum. As shown in our PRISMA flowchart, there was a tendency towards excluding the cerebellum (n=64) or not reporting or discussing cerebellar findings in text even when figures indicated the cerebellum was affected (n=13 for which we could not obtain data even after contacting authors). Twenty-seven studies further indicated potential cerebellar effects but did not report coordinates. These numbers made it clear that this bias in investigating the diseases of interest and in reporting results would inadvertently be translated into a bias in the meta-analytic results when choosing a whole-brain approach.
Given this abundance of studies excluding the cerebellum and underreporting cerebellar findings, it is not surprising that previous meta-analyses did not find robust clusters of cerebellar atrophy. Furthermore, there are additional factors that can explain the apparent lack of GM loss in the cerebellum in the AD, ALS, and FTD meta-analyses.
First, the majority of studies in AD and ALS investigated early stages, during which cerebellar atrophy may not yet be apparent. This tendency to investigate early structural changes may contribute to the belief that the cerebellum is typically spared. Given that clinical assessment using magnetic resonance imaging is carried out early in disease progression and that follow-up scans in clinical practice are rare, later GM loss often remains unexplored. However, neuropathological investigations have found the cerebellum to be affected in AD, ALS, and PSP [9-11]. Second, in our systematic literature search, we contacted authors to obtain additional coordinate data, which was not done in most of the other meta-analyses. The following should emphasize these arguments:
• AD meta-analysis [3]: did not include seven studies present in our analysis; of the 46 AD studies listed in Table 1, n=23 included exclusively early-stage/mild AD, and n=9 studies mild to moderate AD. One study with preclinical AD cases and another with a sample of MSA with dementia would not have met our inclusion criteria [12,13].
• FTD meta-analysis [4]: did not include nine studies from our analysis. 3/9 studies in the whole-brain analysis showed cerebellar atrophy; of the remaining six, n=3 included only patients with mild FTD severity, while n=1 included mild to moderate.
• ALS meta-analysis [5]: did not include two of the studies in our paper. 5/20 studies reported disease-related cerebellar grey matter (GM) or white matter integrity loss; of the other 15, n=10 focussed on patients with mild symptom severity. Interestingly, Minnerop et al. showed a correlation of cerebellar GM loss and disease duration, suggesting that the cerebellum is affected later in the course of ALS [14].
• We would like to point out that the PSP meta-analysis [6], which was cited by Sheng and Pan as not having detected cerebellar GM loss, did find a cluster of atrophy in right declive (see Table 2). This meta-analysis also did not include two of the studies incorporated in our investigation. Cerebellar GM loss was found in 5/12 studies in this meta-analysis, while n=4 of the remaining seven found white matter loss in cerebellar peduncles in the absence of GM differences. Of the three studies with no cerebellar findings, n=2 were in mild PSP.

Finally, we would like to emphasise that we are not claiming that cerebellar atrophy is necessarily present in the majority of patients in all of the investigated diseases. Given that we only selected studies with findings in the cerebellum, we did not seek to determine the likelihood of the cerebellum being affected in a given disease. For our purpose, a focus on studies with cerebellar findings is justified. We conclude that if cerebellar atrophy is present, it follows a disease-specific pattern that tends to correlate with symptomatology in many of the included studies. Our findings demonstrate the importance of future research into the role of the cerebellum in neurodegeneration given the two major issues in the literature which are the tendency to disregard the cerebellum and the vast heterogeneity of patient groups regarding disease stages and subtypes.

Coordinate-based meta-analysis is a powerful way for neuroimaging studies to identify the most consistent and replicable differences in brain activity or structure in neurodegenerative disorders. In their JNNP publication, Gellersen et al 1 conducted coordinate-based meta-analyses of 54 voxel-based morphometry (VBM) studies in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), behavioral variant frontotemporal dementia (bvFTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). In this study, they solely focused on cerebellar grey matter (GM) atrophy.1 Marked cerebellar atrophy in AD, ALS, bvFTD, PSP and MSA, but not in PD or HD, was identified in the meta-analyses.1
These findings are of interest.1 However, the procedure of the meta-analyses had a major limitation. Coordin...

Coordinate-based meta-analysis is a powerful way for neuroimaging studies to identify the most consistent and replicable differences in brain activity or structure in neurodegenerative disorders. In their JNNP publication, Gellersen et al 1 conducted coordinate-based meta-analyses of 54 voxel-based morphometry (VBM) studies in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), behavioral variant frontotemporal dementia (bvFTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). In this study, they solely focused on cerebellar grey matter (GM) atrophy.1 Marked cerebellar atrophy in AD, ALS, bvFTD, PSP and MSA, but not in PD or HD, was identified in the meta-analyses.1
These findings are of interest.1 However, the procedure of the meta-analyses had a major limitation. Coordinate-based meta-analysis is usually used for whole-brain imaging findings. Gellersen et al1 only included the studies that reported coordinates of the cerebellar regions, which resulted in study selection bias in the analyses. This bias may increase the statistical power and the risk of false positive findings in their study. The view is supported by previous meta-analyses in these disorders. Robust cerebellar atrophy was not detected in AD 2, ALS 3, bvFTD 4, PSP 5, PD 6, or HD 7 by previous meta-analyses that included many more whole-brain VBM studies. In contrast, cerebellar atrophy was consistently identified in MSA 5, which was accordant with the meta-analysis by Gellersen et al.1 Thus, selective use of a paticular brain region is not optimal in a coordinate-based meta-analysis.
Based on the current conflicting imaging evidence, it is debatable to consider the existence of cerebellar atrophy in AD, ALS, bvFTD and PSP in VBM studies. As clinical heterogeneity in these disorders and limited by the imaging techniques, further research is warranted to validate cerebellar atrophy in neurodegeneration.

Funding: This work was supported in part by the National Natural Science Foundation of China (Grant No. 81601161).
Competing interests: None.
Contributors: LQS wrote the draft. PLP revised the manuscript.

We thank dr. Coebergh and colleagues for their interest in our study. We agree that(a) there are many differences between the health care systems of the UK and the Netherlands, (b) the results of our study do not apply to excluded patients, and (c) the management of new neurological symptoms, relapses of previous FNS and relevant neurological and other co-morbidities remain very important in order to prevent inappropriate re-referrals and investigations of patients. However, in the absence of sound evidence from appropriate clinical studies,we disagree with the authors’ conclusion that neurological follow-up of these patients is often beneficial.
We wish to emphasize that in our study, firstly a neurologist established the diagnosis and briefly explained the diagnosis to the patient. Secondly, the first neurologist referred the patient to a specially trained second neurologist, who scheduled half an hour to discuss the diagnosis with the patient. This approach is clearly different from immediate referral to a GP after the diagnosis.

It is good to see that trials are being done to answer the critical question of how best to provide care for those patients with functional neurological symptoms (FNS). The research paper, ‘Management of patients with functional neurological symptoms: a single-centre randomised controlled trial’, by Pleizier, de Haan and Vermeulen, randomizes outpatients with functional neurological symptoms after diagnosis, to either two outpatient appointments with a neurologist, or referral back to a GP. Intriguingly, it finds no difference in outcome, that is quality of life scores, between the two groups.[1] While this study attempts to address an important question, namely the role of the neurologist in the care of patients with functional neurological disorders, we feel it has a number of problems that limit its generalizability, particularly to UK neurology practice.
The Netherlands is a country that compared to the UK, has approximately four times as many neurologists per head of the population, and many more GPs with higher levels of job satisfaction,[2] and often have mental health nurse support in the practice itself. Neurology outpatient waiting times are shorter in the Netherlands, and in-patient neurology review happens routinely and is quicker, unlike in the UK where it may not occur at all.[3] Because of this lack of prompt neurological review in the UK, it is common for patients to receive erroneous diagnoses, often necessitating an “undiagnosis” at the eventual neu...

It is good to see that trials are being done to answer the critical question of how best to provide care for those patients with functional neurological symptoms (FNS). The research paper, ‘Management of patients with functional neurological symptoms: a single-centre randomised controlled trial’, by Pleizier, de Haan and Vermeulen, randomizes outpatients with functional neurological symptoms after diagnosis, to either two outpatient appointments with a neurologist, or referral back to a GP. Intriguingly, it finds no difference in outcome, that is quality of life scores, between the two groups.[1] While this study attempts to address an important question, namely the role of the neurologist in the care of patients with functional neurological disorders, we feel it has a number of problems that limit its generalizability, particularly to UK neurology practice.
The Netherlands is a country that compared to the UK, has approximately four times as many neurologists per head of the population, and many more GPs with higher levels of job satisfaction,[2] and often have mental health nurse support in the practice itself. Neurology outpatient waiting times are shorter in the Netherlands, and in-patient neurology review happens routinely and is quicker, unlike in the UK where it may not occur at all.[3] Because of this lack of prompt neurological review in the UK, it is common for patients to receive erroneous diagnoses, often necessitating an “undiagnosis” at the eventual neurology review.[4] Given these starkly different clinical contexts, we believe that a single neurology appointment in the UK, as compared to neurological follow-up for patients with FNS, would not lead to similar outcomes as published in this study.
Not withstanding these cultural differences, there is also significant, multi-faceted selection bias in this study, which limits the interpretation of the results. Firstly, the authors only include patients referred by GPs in this study. In our experience, patients that come via A&E or have been recently discharged from hospital are different to those referred by GPs, having had more investigations, and have more severe symptoms and a poorer prognosis if there is
no improvement in hospital.[5] The authors also exclude patients who have been symptomatic for over a year. In reality, this would mean the exclusion of large numbers of patients. Indeed in this study 923/1147 patients are excluded for this very reason,[1] and the proportion of patients is likely to be higher in the UK for the reasons of delayed diagnosis explained above. It is likely that the longer patients are symptomatic with FNS, the poorer their prognosis.[6] These strict criteria therefore exclude the very patients who need treatment and follow-up care most, and are likely to bias the results of this study, and limit its interpretability when applied to the broader population of patients with FNS.
Lastly, a single neurologist accounted for treatment of 90% of the patients in the intervention arm of the study. It is therefore conceivable that the (high) standard of care received by patients from this neurologist who had a specific interest in FNS reduced any additional benefit from further neurology follow-up appointments. Indeed 34% of the patients who were supposed to receive at least 2 follow-up appointments failed to do so either because they thought it was unnecessary, or because they did not attend the follow-up appointments. The generalizability of these findings must therefore be in question.
The authors suggest many useful ideas for future studies. However, the variability present in their approach to follow up appointments and the use of physiotherapy and psychotherapy, demonstrates that ultimately, individualized treatment and follow up plans remain the gold standard in this complex group of patients with competing biological, psychological and social factors relevant to their FNS. Furthermore, the management of new neurological symptoms, relapses of previous FNS and relevant neurological and other co-morbidities remains very important in order to prevent inappropriate re-referrals and investigations of patients.[7] For these reasons and those discussed above, we believe that neurological follow-up of these patients is often beneficial.
Reference list
1. Pleizier M, de Haan RJ, Vermeulen M. Management of patients with functional neurological symptoms: a single-centre randomised controlled trial. J Neurol Neurosurg Psychiatry. 2017;88(5):430-436.
2. Arie S. Why are Dutch GPs so much happier? BMJ. 2015;351:h6870.
3. Gregory R, Nicholl D, Lawrence J, et al. Association of British Neurologists (ABN) 2017 Acute Neurology Survey. March 2017.
4. Coebergh JA, Wren DR, Mumford CJ. ‘Undiagnosing’ neurological disease: how to do it, and when not to. Practical Neurology. 2014;14:436-439.
5. Couprie W, Wijdicks EF, Rooijmans HG, et al. Outcome in conversion disorder: a follow up study. J Neurol Neurosurg Psychiatry. 1995;58(6):750-2.
6. Gelauff J, Stone J, Edwards M, et al. The prognosis of functional (psychogenic) motor symptoms: a systematic review. J Neurol Neurosurg Psychiatry. 2014;85(2):220-6.
7. Crimlisk HL, Bhatia KP, Cope H, et al. Patterns of referral in patients with medically unexplained motor symptoms. J Psychosom Res. 2000;49(3):217-9.